Amyloid β-Exposed Human Astrocytes Overproduce Phospho-Tau and Overrelease It within Exosomes, Effects Suppressed by Calcilytic NPS 2143-Further Implications for Alzheimer's Therapy.
Amyloid β-Exposed Human Astrocytes Overproduce Phospho-Tau and Overrelease It within Exosomes, Effects Suppressed by Calcilytic NPS 2143-Further Implications for Alzheimer's Therapy.
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DOI：
10.3389/fnins.2017.00217
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发表时间：
2017
影响因子：
4.3
通讯作者：
Dal Prà I
中科院分区：
文献类型：
--
作者：
Chiarini A;Armato U;Gardenal E;Gui L;Dal Prà I
阿尔茨海默病(AD)的两个主要驱动因素--淀粉样蛋白β(Aβ)和过度磷酸化的Tau(p-Tau)寡聚体协同加速AD的进展，但关于两者中哪一个最先出现仍存在激烈的争论。在这里，我们提出的初步证据表明，在培养的未转化的成人皮质星形胶质细胞表达Tau和p-Tau，这些细胞暴露于Aβ42的替代物Aβ25−35，它结合钙敏感受体(CaSR)并激活其信号转导，显著增加细胞内p-Tau的水平，CaSR拮抗剂(钙溶)NPS2143完全阻止这种作用。星形胶质细胞还通过外切体将Tau和p-Tau释放到细胞外介质中，这一活动可能会介导p-Tau在脑内的扩散。初步数据还表明，在Aβ25−35暴露后，p-Tau的外体水平增加，但在加入Aβ25−35之前用NPS2143预处理30分钟的细胞中，p-Tau水平保持不变。因此，我们以前和现在的发现提出了一个统一的前景，即Aβ·CaSR信号通过同时激活(I)淀粉样前体完整蛋白的淀粉样蛋白的形成过程和(Ii)β-3β介导的p-Tau寡聚体的产生增加而在AD的发生和进展中发挥关键作用，该过程的结果是A Tau 42寡聚体的过剩生产和分泌，这些寡聚体下一步在胞外释放到外体内。因此，由于溶钙剂抑制了对Aβ42和p-β代谢处理的影响，这些高度选择性的病理性A Tau·CaSR信号拮抗剂将有效地阻止AD的进展，保护患者的认知和生活质量。
The two main drivers of Alzheimer's disease (AD), amyloid-β (Aβ) and hyperphosphorylated Tau (p-Tau) oligomers, cooperatively accelerate AD progression, but a hot debate is still ongoing about which of the two appears first. Here we present preliminary evidence showing that Tau and p-Tau are expressed by untransformed cortical adult human astrocytes in culture and that exposure of such cells to an Aβ42 proxy, Aβ25−35, which binds the calcium-sensing receptor (CaSR) and activates its signaling, significantly increases intracellular p-Tau levels, an effect CaSR antagonist (calcilytic) NPS 2143 wholly hinders. The astrocytes also release both Tau and p-Tau by means of exosomes into the extracellular medium, an activity that could mediate p-Tau diffusion within the brain. Preliminary data also indicate that exosomal levels of p-Tau increase after Aβ25−35 exposure, but remain unchanged in cells pre-treated for 30-min with NPS 2143 before adding Aβ25−35. Thus, our previous and present findings raise the unifying prospect that Aβ•CaSR signaling plays a crucial role in AD development and progression by simultaneously activating (i) the amyloidogenic processing of amyloid precursor holoprotein, whose upshot is a surplus production and secretion of Aβ42 oligomers, and (ii) the GSK-3β-mediated increased production of p-Tau oligomers which are next released extracellularly inside exosomes. Therefore, as calcilytics suppress both effects on Aβ42 and p-Tau metabolic handling, these highly selective antagonists of pathological Aβ•CaSR signaling would effectively halt AD's progressive spread preserving patients' cognition and life quality.